von Langen, Johannes;Diekmann, Stephan;Hillisch, Alexander - Homology modeling and molecular dynamics simulation of the human androgen receptor ligand binding domain

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Title: Homology modeling and molecular dynamics simulation of the human androgen receptor ligand binding domain	P171
von Langen, Johannes; Diekmann, Stephan; Hillisch, Alexander langen@imb-jena.de Jena Centre for Bioinformatics (JCB), Institut für Molekulare Biotechnologie Jena, Beutenbergstr. 11, D-07745 Jena, EnTec GmbH, Adolf-Reichwein-Str. 20, D-07745 Jena

The genome sequencing projects provided us with tremendous amounts of protein sequence information. However, to elucidate and understand the function of these proteins, structural information is essential. In general, protein structure is determined by x-ray crystallography and NMR spectroscopy. Nevertheless, for only about one percent of the known proteins an experimentally determined structure is available [1]. Homology modeling helps to fill this sequence-structure gap. The quality of the computed models strongly depends on the sequence identity between target and template. Highly accurate models can be built if this sequence identity exceeds 50 %.

Receptor structure:
We have built a homology model of the human androgen receptor (hAR) ligand binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR) [2]. Our goal is to get an in-depth understanding on the binding mode of the steroid testosterone to its receptor (the androgen receptor). Our homology model of the human androgen receptor is compared with the x-ray structure of the rat androgen receptor [3] which was published later. The amino acid sequence of the rAR is 100% identical to that of the hAR and serves as an ideal reference for correct modeling.

Ligand binding dynamics:
In order to predict the binding mode of testosterone to the hAR, we performed a 2 ns molecular dynamics (MD) simulation of the homology modeled protein-ligand complex in aqueous environment. Testosterone was placed in the hAR binding pocket as progesterone is positioned in hPR. When placed in this way, testosterone was found not to form all important interactions with its receptor. During the MD simulation, however, testosterone binding changes and adopts a binding mode as optimal as observed in the rAR X-ray structure. We also present here an analysis of the trajectory of the hAR-LBD with respect to the crystal structure. This allows to characterise the flexibility of functionally important amino acids involved in ligand and coactivator binding.

In conclusion, the structure of the hAR-LBD and the interactions with its natural ligand testosterone was predicted with high accuracy. This paves the way for homology modeling of other members of the nuclear receptor family and the structure-based design of ligands.

[1] A. Hillisch, R. Hilgenfeld, The role of protein 3D-structures in the drug discovery process, in: Modern Methods of Drug Discovery, eds. Hillisch A., Hilgenfeld, R., Birkhäuser Publishing Ltd., Basel, 2002, in press.
[2] S. P. Williams, P. B. Sigler, Atomic structure of progesterone complexed with its receptor (1998) Nature 393, 392-396.
[3] J. S. Sack, et. al. Crystallographic structures of the ligand-binding domain of the androgen receptor and its T877A Mutant complexed with the natural agoinst (2001) PNAS 98, 4904-4909.